Inhibition of liver carboxylesterases by various pesticidal and nonpesticidal compounds potentiate the in vivo anticholinesterase action of several phosphorothionate insectisides either by inhibiting hydrolytic detoxication of carboxy ester linkages in the insecticides or by reducing non-critical binding sites which otherwise spare vital cholinesterase from inhibition. However, other, as yet unidentified, mechanisms appear to contribute to marked potentiation of some insecticides (e.g. Guthion; azinphosmethyl) by certain carboxylesterase inhibiting compounds (e.g. triorthotolphosphate (TOTP); S,S,S-tributyl phosphorothionate (DEF). Investigations of mechanisms to explain the potentiation of diethyl phosphorothionates (DEPs) and antagonism of dimethly phosphorothioates (DMPs) by piperonly butoxide (PB) pretreatment have been conducted. Results suggest that PB inhibits both oxidative activation and detoxification pathways for both DMPs and DEPs. However, because glutathione dealkylation provides an alternate pathway of detoxification for DMPs and because the rate of reversal cf cholinesterase inhbitied by DMPs is more rapid than for DEPs, the net effect of PB is to shift the balance toward reduced toxicity for DMPs and toward increased toxicity for DEPs. Dose and time response studies for cholinesterase inhibition after dermal exposure to methyl parathion, indicate marked anticholinesterase action of this compound in rats in the absence of signs of poisoning. Further studies to compare relationships between rates and degrees of cholinesterase inhibition and toxic signs by different routes of exposure for methyl parathion and related compounds are in progress. These studies of biochemical mechanisms of interactions among different compounds and by different compounds and by different routes should provide useful information for predicting conditions or unusual susceptibility of humans that may be accidentally or occupationally exposed to OP insecticides. BIBLIOGRAPHIC REFERENCES: Benke, G.M. and Murphy, Sheldon D.: The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats. Toxicol. Appl. Pharmacol. 31:254-269, 1975. Chow, A.Y.K. and Murphy, Sheldon D.: Production of a methemoglobin forming metabolite of 3,4-dichloroaniline by liver in vitro. Bull. Env. Cont. Toxicol. 13:9-13, 1975.